The long-term objectives of this proposal are to continue to study circadian and seasonal fluctuations of gastrointestinal peptides and factors that influence circadian variation of storage, release, and actions of GI peptides. Emphasis will be placed on GI peptides as they relate to normal and pathological states of GI function in animals and on studies to determine hormonal and cellular mechanisms that control rhythms of GI peptides. One aim of this proposal is to study obesity, which is a major nutritional disorder in the United States and many parts of the industrialized world. Consumption of excess calories, attributed to the failure of regulatory mechanisms of eating behavior, leads to accumulation of body weight and adipose tissue. A number of peptide hormones exert significant effects on food intake and satiety. Investigations will be conducted in genetic and stress-induced obese rats to determine the relation between circadian and seasonal fluctuations of GI peptides and circadian and seasonal changes in dietary intake. Dehydroepiandrosterone is a steroidal agent that induces weight loss without affecting food intake. The direct effect of this agent on obesity will also be investigated to further study obesity and its relation to circadian variation in GI hormone physiology. The relationship of GI peptide rhythms to various disease states, such as pancreatic insufficiency and ulcer disease, will also be examined, and studies will be conducted to determine temporal influences of various peptides and chemotherapeutic agents on GI disorders. Isolated rat pancreatic acinar cells will be studied to determine whether pancreatic exocrine secretions and factors that modulate these secretions are influenced by circadian system. Specific agonists and antagonists will be used in these studies. The chronobiologic effects of the administration of hormones, their agonists and antagonists, on their trophic and antitropic actions on the mucosa of the gut will be tested in rodents. Temporal changes in DNA synthesis will be related to rhythmicity in peptide levels in tissue and plasma. Pacemaking factors in the control of circadian rhythms will be investigated by examining the role of the pineal gland, adrenal gland, gonads, and pituitary gland on fluctuations in GI peptide hormones. The successful completion of studies planned in this proposal will extend our knowledge of temporal factors contributing to normal function of the GI tract and will provide information that could be of major medical consequence.